All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Neutrophils, the most common granulocytes, constitute up to 70% of circulating leukocytes that primarily defend against pathogen infections. Cancer chemotherapy-induced neutropenia is a hematological disorder marked with a significant decrease in the number of neutrophils in the bloodstream, leading to susceptibility to microbial infections. About 15-40% of cancer patients require treatment delay and/or dose reduction because of chemotherapy-induced neutropenia. Mortality rate due to neutropenia is about 5% in patients with solid tumors and 11% in some hematological malignancies.
Neutrophil production requires balanced proliferation and differentiation during granulopoiesis of hematopoietic stem cells (HSC). GCSF has been used to treat acquired and congenital neutropenia for more than two decades as it promotes granulopoiesis of HSC to regenerate neutrophils. However, the large numbers of neutrophils regenerated in response to GCSF administration are immature, thus resulting in an ineffective GCSF therapy that fails to reduce both infection and infection-related mortality of cancer chemotherapy-induced neutropenia (CCIN) patients. Evidence supports that the cost-effectiveness of primary prophylactic use of GCSF for CCIN is inconclusive, and recent studies have shown that primary prophylactic use of GCSF during the first course of chemotherapy was associated with a 57% increase in overall healthcare costs. In the US, the cost of CCIN ranged from $1,893 per outpatient episode to $38,583 per febrile neutropenia hospitalization. Substantial differences in the clinical and economic burden of CCIN exist depending on cancer types, co-morbidities and types of infections. Owing to the decreased inflammatory response in CCIN, the symptoms and signs of infection are attenuated or even absent. Hence, chemotherapy comprises the majority of costs for both febrile neutropenia (33.5%) and non-febrile neutropenia (40.6%) patients. The estimated cost for febrile neutropenia hospitalization (FNH) only for 2015 is about $2.1 billion. This cost does not include the cost for treatment of non-febrile neutropenia, relapsed cancer patients requiring new chemotherapy, congenital neutropenia, idiopathic severe chronic neutropenia, cyclic neutropenia, and radiation-induced neutropenia. Hence, despite preventive use of GCSF, neutropenia still remains a devastating issue for cancer patients, with substantial morbidity, mortality, and healthcare cost. As such, alternative modes of treatment are urgently needed for these neutropenic patients.
Herein, the inventor demonstrates synergistic effect of a combination of a retinoid agonist (e.g., Am80) and G-CSF on reducing infection and infection-related mortality. For treating neutropenia and neutropenia-related conditions, provided herein are compositions, methods and kits that capitalize on the synergistic effect of retinoid agonist (e.g., Am80) with G-CSF on regeneration of mature neutrophils against infection and infection-related mortality.